Early preclinical development of Mycobacterium tuberculosis amino acid biosynthesis pathway inhibitor DRILS-1398 as a potential anti-TB drug

• Published in: iScience Vol. 28; no. 6; p. 112537
• Main Authors: Biswas, Deepesh, Edwin, Rebecca Kristina, Kumar, K. Shiva, Alam, Anwar, Kumar, Dhiraj, Chakraborty, Sandipan, Bulusu, Gopalakrishnan, Ahmad, Farhan Jalees, Shenoy, Gautham G., Singh, Lakshyaveer, Agarwal, Mansi, Siraj, Fouzia, Oruganti, Srinivas, Misra, Parimal, Ehtesham, Nasreen Zafar, Pal, Manojit, Hasnain, Seyed Ehtesham
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.06.2025; Elsevier
• Subjects: Biological sciences; Medical Microbiology; Microbiology; Natural sciences; Pharmacology; Medical Microbiology; Biological sciences; Pharmacology; Microbiology; Natural sciences
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2025.112537

The search for new anti-tubercular agents is vital for the fight against Mycobacterium tuberculosis, particularly given the rise of drug-resistant strains. DRILS-1398, a pyrazolo[4,3-d]pyrimidine derivative, was discovered as a potent inhibitor of M.tb chorismate mutase (M.tb-CM) with an IC50 = 3.0 ± 0.2 μM (n = 3) and IC90 = 10 μM. The compound demonstrated efficacy against multi-drug resistant M.tb strains (MIC = 4 μg/mL, ∼10.0 μM) and effective inhibition of intracellular M.tb in THP-1 macrophages. With favorable pharmacokinetics, moderate stability in vitro, and a promising safety profile, DRILS-1398 showed no toxicity at doses up to 500 mg/kg b.w./day when dosed orally daily once for 7 consecutive days in mice. Both DRILS-1398 and its formulation DRILS-1398(F) were successful in clearing M.tb infection from the lungs and spleen in murine models. These findings suggest DRILS-1398 as a promising lead candidate for developing a first-in-class anti-tubercular drug. [Display omitted] •DRILS-1398 is a 1st in class inhibitor of M.tb amino acid biosynthetic pathway•DRILS-1398 is effective against intracellular MDR-M.tb•Formulated DRILS-1398 elicits superior pharmacokinetics properties and efficacy•DRILS-1398 is safe, non-toxic, and well-tolerated in animal models Biological sciences; Medical Microbiology; Microbiology; Natural sciences; Pharmacology